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Pharmacologic therapy

TL;DR — No drug works well for most fibromyalgia patients; a minority get worthwhile relief from any given agent. The best-evidenced drugs (duloxetine, milnacipran, pregabalin) deliver ≥30% pain relief to roughly 10% more patients than placebo (NNT ~6–14), with adverse-event dropout NNHs of ~7–14 (Welsch 2018, PMID 29489029; Derry 2016, PMID 27684492; Cording 2015, PMID 26482422). The FDA approved pregabalin, duloxetine, and milnacipran (2007–2009) and, in August 2025, a fourth drug — sublingual cyclobenzaprine (TNX-102 SL/Tonmya) (Abd-Elsayed 2026, PMID 42479282) — while European regulators rejected all fibromyalgia indications, so no drug is approved for FM in the EU (Briley 2010, PMID 20047155; Calandre 2015, PMID 26001183; Sullivan 2026, PMID 41948806). Amitriptyline remains first-line in most guidelines on decades-old, small, biased trials (NNT ~4 but "very low quality"; Moore 2015, PMID 35658166). Strong opioids, NSAIDs, and corticosteroids do not work and can harm. Real-world adherence is poor: only ~33% of duloxetine initiators are adherent at 1 year (Cui 2012, PMID 22792005). The biggest open question is not which drug is best but whether any drug's average effect justifies population-level use — versus better targeting of the minority who respond.

The scoreboard: effect sizes, not adjectives

Drug Regulatory status (FM) ≥30% pain relief (drug vs placebo) ≥50% pain relief Key harms (NNH) Evidence quality Source
Amitriptyline 25–50 mg Off-label, guideline first-line — (not reliably reported) RR 3.0 (1.7–4.9), NNT 4.1 (2.9–6.7) ≥1 AE: NNH 3.3 Very low (third-tier; 9 studies, 649 pts, none >50/arm) Moore 2015, PMID 35658166
Duloxetine 60 mg FDA 2008; EMA refused NNTB 10 (with milnacipran, pooled) RR 1.57, NNTB 8 (4–21) at 12 wk AE dropout NNTH 14 (SNRI pooled) Low–moderate Lunn 2014, PMID 24385423; Welsch 2018, PMID 29489029
Milnacipran 100–200 mg FDA 2009; EMA refused 40% vs 30%; NNT 6–10 Insufficient data Nausea NNH 5.7; AE dropout NNH 14 (100 mg), 7 (200 mg) High for the modest effect Cording 2015, PMID 26482422
Pregabalin 300–600 mg FDA 2007; EMA refused 39–43% vs 28%; NNT ~9 (range 7–14) 22–24% vs 14% (450 mg RR 1.8) Dizziness NNH 3.7; somnolence 7.4; weight gain 18 High Derry 2016, PMID 27684492
Gabapentin Off-label 49% vs 31% (1 trial, n=150) Not reported AE dropout 16% vs 9% Very low Cooper 2017, PMID 28045473
Cyclobenzaprine (oral) Off-label Global improvement OR 3.0; NNT 4.8 — — (harms not quantified in meta) 5 small RCTs (2004 meta) Tofferi 2004, PMID 14872449
TNX-102 SL 5.6 mg (sublingual cyclobenzaprine) FDA approved 2025 (Tonmya) RR 1.44 (1.15–1.81) RR 1.43 (1.12–1.82) Oral hypoesthesia RR 38.1; dropout ≈ placebo 4 RCTs, n=1,684 (meta) Al-Qudah 2025, PMID 41318845
SSRIs Off-label NNTB 10 (5–100) — Dropout ≈ placebo Very low Walitt 2015, PMID 26046493
Tramadol ± paracetamol Off-label Positive signal, 4 RCTs (n=459) — — Low (GRADE) da Rocha 2020, PMID 31799728

Cross-drug network meta-analyses reach the same verdict from a different direction: across 102 trials/14,982 patients, drug benefits were statistically significant but "small and not clinically relevant" when analysis was restricted to large trials (Nüesch 2013, PMID 22739992); across 176 antidepressant trials in chronic pain (59 in FM), duloxetine was the only drug with moderate-certainty evidence, with standard dose (60 mg) as effective as high dose (Birkinshaw 2023, PMID 37160297).

Amitriptyline: first-line by tradition, not by trial quality

The Cochrane review found no first- or second-tier evidence at all: nine studies, 649 participants, none with ≥50 per arm, 6–24 weeks, doses 25–50 mg. Third-tier analysis gives RR 3.0 (95% CI 1.7–4.9) for ≥50% pain relief, NNT 4.1 (2.9–6.7) — nominally the best NNT in fibromyalgia — but the authors' explicit concern is overestimation of effect; 78% had ≥1 adverse event vs 47% on placebo (NNH 3.3) (Moore 2015, PMID 35658166). The 2009 JAMA meta-analysis quantified the same asymmetry: pooled TCA effect size for pain was SMD −1.64 (−2.57 to −0.71) from small old trials, versus −0.36 for SNRIs and −0.39 for SSRIs from large modern ones (Häuser 2009, PMID 19141768). Large, modern amitriptyline RCTs will likely never be run (Moore 2015, PMID 35658166), so guidelines keep recommending a drug whose true effect size is unknown — a structural evidence gap worth remembering when guidelines rank it "highest recommendation" (guidelines).

SNRIs: duloxetine and milnacipran

Pooled SNRI data (18 studies, 7,903 participants): ≥30% pain relief RD 0.10, NNTB 10; ≥50% relief 31% vs 21%, RD 0.09, NNTB 11 — judged not clinically relevant by the review's threshold for the 50% outcome; PGIC much/very much improved 52% vs 29% (NNTB 5). No clinically relevant benefit for fatigue (NNTB 18), sleep (no difference), or HRQoL (NNTB 11). AE dropout 19% vs 10% (NNTH 14). The authors' summary sentence is unusually blunt: on average, potential benefits were outweighed by potential harms, but "a minority ... might experience substantial symptom relief without clinically relevant adverse events" (Welsch 2018, PMID 29489029).

  • Duloxetine: ≥50% relief at 12 weeks RR 1.57 (1.20–2.06), NNTB 8 (4–21); effect maintained at 28 weeks (RR 1.58); effect sizes similar at 60 and 120 mg; the pivotal trial found pain reduction independent of mood effects and of baseline depression status (Lunn 2014, PMID 24385423; Arnold 2005, PMID 16298061 — ≥30% response 55%/54% vs 33%). The 2023 Cochrane NMA ranks duloxetine first among all antidepressants for chronic pain, with moderate certainty, OR 1.91 (1.69–2.17) for substantial relief (Birkinshaw 2023, PMID 37160297).
  • Milnacipran: ≥30% relief ~40% vs 30% (NNT 6–10, high-quality for this modest claim); stricter responder definitions drop response to 26% vs 17% (NNT 11); LOCF imputation likely inflates all of these. Nausea NNH 5.7; AE withdrawal NNH 7 at 200 mg (Cording 2015, PMID 26482422). The pivotal registration trial prospectively used composite responders targeting two potential indications, "FM" and "FM pain" (pain + PGIC ± SF-36 PCS), with AE discontinuation 19.5–23.7% vs 9.5% (Clauw 2008, PMID 19108787) — see outcomes-and-measurement for the composite-endpoint story.

Gabapentinoids: pregabalin and gabapentin

Pregabalin has the largest and cleanest trial program (8 studies; 5 classic-design, 3,283 patients). At 300–600 mg: ≥50% relief in 22–24% vs 14% (450 mg RR 1.8, 1.4–2.1); ≥30% relief 39–43% vs 28%; NNTs 7–14 — i.e., ~1 in 10 patients gains substantial benefit attributable to drug, high-quality evidence. Harms are the mirror image: dizziness NNH 3.7, somnolence 7.4, weight gain 18, peripheral edema 19; 70–90% of all arms had ≥1 AE (Derry 2016, PMID 27684492). The pivotal trial: 450 mg reduced mean pain −0.93/10 vs placebo; ≥50% response 29% vs 13% (Crofford 2005, PMID 15818684). In responders, benefit is durable: in the 6-month enriched-withdrawal FREEDOM trial, median time to loss of response was 19 days on placebo, not reached on pregabalin; 61% vs 32% lost response by 26 weeks (Crofford 2008, PMID 18400400) — but only ~54% of the 1,051 entering open-label titration responded well enough to be randomized, and in the Cochrane pooled analysis of the two EERW trials, normalizing the maintained-response NNT to the starting population raises it from 5 to 12 (Derry 2016, PMID 27684492).

Gabapentin, widely assumed interchangeable, has essentially no FM evidence: one 12-week trial (n=150; ≥30% relief 49% vs 31%; PGIC "better" 91% vs 47%) rated very low quality; conclusion "insufficient evidence to support or refute" (Cooper 2017, PMID 28045473).

Cyclobenzaprine — and the 2025 approval of its sublingual reformulation

Oral cyclobenzaprine (a TCA-like muscle relaxant): 5 RCTs, global improvement OR 3.0 (1.6–5.6), NNT 4.8 (3.0–11); pain improved early; fatigue and tender points did not (Tofferi 2004, PMID 14872449). Patients rank it among their most used and most effective drugs (Bennett 2007, PMID 17349056).

TNX-102 SL (Tonmya) is a 2.8/5.6 mg bedtime sublingual cyclobenzaprine formulation engineered for transmucosal absorption (bioavailability ~154% of oral IR, absorption lag ~3 min vs ~37 min; first characterization of the ~60 h half-life active metabolite norcyclobenzaprine) (Daugherty 2026, PMID 41749492). Its mechanism is framed as targeting non-restorative sleep (sleep-fatigue-cognition). Trial record:

Trial n Primary endpoint (daily pain, week 14) Result
RELIEF (phase 3) 503 LS mean change −1.9 vs −1.5 p=0.01; PGIC not significant; FIQR, PROMIS sleep/fatigue improved (Lederman 2023, PMID 37165930)
RESILIENT (phase 3, NCT05273749) 456 −1.8 vs −1.2 p<0.001; all 6 secondary endpoints met, incl. PGIC and FIQR (Lederman 2026, PMID 40627411)

Meta-analysis of 4 RCTs (n=1,684): ≥30% responders RR 1.44 (1.15–1.81); ≥50% RR 1.43 (1.12–1.82); PGIC RR 1.52; pooled pain SMD −0.25 (−0.34 to −0.16) — i.e., a between-drug effect size in the same modest range as the existing approved drugs; FIQR not significant in one meta; local oral AEs dominate (hypoesthesia RR 38.1, paresthesia RR 7.9, dysgeusia RR 10.9) but discontinuation equals placebo (RR 1.03) (Al-Qudah 2025, PMID 41318845; Maggi 2025, PMID 41047726). FDA approval as Tonmya came in August 2025, under the 505(b)(2) pathway ("TNX-102 SL, approved as TONMYA"; Sullivan 2026, PMID 41948806; approval month and "first new pharmacologic treatment approved for FM in more than 15 years": Abd-Elsayed 2026, PMID 42479282) — the first new FM approval since milnacipran in 2009, and the first centered on a sleep-targeting mechanism. Note the asymmetry: a −0.6/10 drug–placebo difference earned approval in 2025, while EMA rejected drugs with similar deltas in 2009–2010 (below).

SSRIs, tramadol, sodium oxybate

  • SSRIs (citalopram, fluoxetine, paroxetine; 7 studies, 383 patients): ≥30% relief RD 0.10 (NNTB 10, 95% CI 5–100); no effect on fatigue or sleep; antidepressant effect present (NNTB 13 for depression). All studies had ≥1 major bias source; verdict: "no unbiased evidence" for core symptoms (Walitt 2015, PMID 26046493).
  • Tramadol (weak opioid + monoamine reuptake inhibition): 4 RCTs, n=459; positive pain signal alone or with paracetamol; FIQ benefit only for the combination; GRADE low; "not sufficient to support or refute" routine use (da Rocha 2020, PMID 31799728). The largest single trial: tramadol 37.5 mg/paracetamol 325 mg combination tablets, 91-day double-blind RCT (n=315) — fewer all-cause discontinuations (48% vs 62%, p=0.004), less end-of-study pain (53 vs 65 on 0–100 VAS), better FIQ (p=0.008); AE discontinuation 19% vs 12% (Bennett 2003, PMID 12753877). Canadian guidelines reserve a weak-opioid (tramadol-first) trial for moderate–severe pain unresponsive to other therapy, while discouraging strong opioids (Fitzcharles 2013, PMID 23748251).
  • Sodium oxybate improved a composite of pain, FIQ, and PGIC in an 8-week multicenter RCT (n=188) (Russell 2009, PMID 19116896) but was never approved for FM: the FDA declined the indication in 2010 "mostly because of concerns about abuse" and set a high bar (superior efficacy plus risk-mitigation) for any resubmission (Staud 2011, PMID 21679091); European authorization was likewise refused ("Sodium oxybate: not authorised for fibromyalgia," Prescrire Int 2012, PMID 23373093; Calandre 2015, PMID 26001183).

What fails or harms

Intervention Evidence Verdict
Strong opioids No RCT evidence at all (oxycodone review: zero eligible trials; Gaskell 2016, PMID 27582266). Observational data: opioid users have poorer outcomes than non-users; use remains common (Goldenberg 2016, PMID 26975749) Recommended against by essentially all guidelines; German S3 explicitly "strong opioids not recommended" (Sommer 2017, PMID 28493231)
NSAIDs 6 RCTs, n=292 (etoricoxib, ibuprofen 2400 mg, naproxen, tenoxicam): no difference from placebo on any outcome, very low quality — but bias should have favored NSAIDs and still showed nothing (Derry 2017, PMID 28349517) Ineffective; mechanistically predictable given non-inflammatory nociplastic pain (pathophysiology-central)
Corticosteroids Prednisone 15 mg/day, 14-day double-blind crossover (n=20): no improvement, trend toward deterioration (Clark 1985, PMID 3910836) No role; never retested at scale

Patients' own rankings invert this evidence: in a 2,596-respondent survey, hydrocodone, oxycodone, and benzodiazepine-class drugs were perceived as most effective, and NSAIDs/acetaminophen were among the most used (Bennett 2007, PMID 17349056) — a persistent gap between trial evidence and lived treatment landscape (patient-experience-and-advocacy).

Cannabinoids: honest uncertainty

Cochrane (2016) found only two nabilone RCTs (n=72), very low quality, with poor tolerability — "no convincing, unbiased, high quality evidence" (Walitt 2016, PMID 27428009). A 2022 meta-analysis of 8 RCTs (n=240) in chronic primary pain (several in FM; FIQ was a prespecified secondary outcome) found no significant pain reduction overall (VAS MD −0.64, 95% CI −1.30 to 0.02) with a possible effect only in >4-week parallel trials (MD −1.28, −2.33 to −0.22), low-quality evidence throughout (Giossi 2022, PMID 36129666). Widespread patient use (medical cannabis programs list FM among top indications) is running far ahead of trial evidence; adequately powered RCTs of standardized products are the outstanding need.

Low-dose naltrexone: a cautionary arc

  • Pilot era: 4.5 mg LDN beat placebo in a 31-woman crossover trial (28.8% vs 18.0% baseline pain reduction, p=0.016) with excellent tolerability (Younger 2013, PMID 23359310), triggering a decade of off-label enthusiasm.
  • Confirmatory era: the adequately powered Danish trial (n=99, 6 mg, 12 weeks) found no significant benefit: between-group difference −0.34 (95% CI −0.95 to 0.27), p=0.27, Cohen's d 0.23; a possible memory signal was hypothesis-generating only (Bruun 2024, PMID 38258677).
  • Synthesis: meta-analysis of RCTs still finds a small pooled FM effect vs placebo (d = −0.34, p=0.019) but nothing vs active comparators, with more adverse events than placebo (IRR 1.4) (Hegde 2025, PMID 40540205); a 2026 review of 105 LDN studies across indications concludes early positive findings were "rarely replicated in placebo-controlled trials" and current evidence does not support routine use (Gouda 2026, PMID 42060160).

Combination therapy

The only rigorous combination trial: pregabalin + duloxetine (double-blind, 4-period crossover, n=41). Daily pain 3.7 (combination) vs 4.1 (duloxetine), 5.0 (pregabalin), 5.1 (placebo); ≥moderate global relief 68% vs 42%/39%/18%; FIQ, SF-36, sleep, and depression all favored combination, at the cost of more moderate–severe drowsiness (Gilron 2016, PMID 26982602). The Cochrane review of all combination pharmacotherapy (16 studies, 1,474 participants) could not meta-analyze anything — heterogeneous pairs, small trials, very low quality — and found only three trials suggesting combination beats monotherapy (melatonin+amitriptyline, fluoxetine+amitriptyline, pregabalin+duloxetine) (Thorpe 2018, PMID 29457627). Given that most treated patients are on ≥2 CNS-active drugs in practice [unverified], this is one of the field's most consequential evidence holes.

Real-world use and discontinuation

Trial NNTs assume patients keep taking the drug; most do not. Among 4,660 commercially insured US patients initiating duloxetine for FM, only 33% achieved adherence (MPR ≥0.8) over 1 year; prior antidepressant use and older age predicted persistence (Cui 2012, PMID 22792005). In employer data, pregabalin vs antidepressant standard-of-care initiators showed no adherence advantage for either (Kleinman 2011, PMID 21392253). Trial AE-dropout NNHs of 7–14 (above) compound with real-world attrition, so the effective population benefit of FM pharmacotherapy is well below what pivotal trials advertise. Placebo/nocebo mechanics account for much of both arms of the ledger: ~19% of placebo-treated trial patients achieve ≥50% relief and ~11% drop out of placebo arms for adverse events (Häuser 2012, PMID 23137770) — see outcomes-and-measurement.

The regulatory split: FDA yes, EMA no

FDA approved pregabalin (2007), then duloxetine and milnacipran within 18 months; the European regulators subsequently rejected all three FM indications, despite the same drugs being marketed in Europe for other indications (Briley 2010, PMID 20047155). A decade later the asymmetry persisted: "only three ... approved by the US FDA, and none ... by the European Medicines Agency" (Calandre 2015, PMID 26001183). The editorial record frames the divergence as differing regulatory weighting of the same modest evidence — small mean pain deltas judged against a high placebo response (Briley 2010, PMID 20047155 [abstract-consistent; full text not retrievable this session]; placebo magnitudes quantified in Häuser 2012, PMID 23137770). The consequence is a transatlantic natural experiment — identical evidence, opposite labels — now sharpened by NICE's 2021 chronic-primary-pain guideline, under which antiepileptic drugs (the class including pregabalin), NSAIDs, benzodiazepines, and opioids "should not be offered" — in the same era in which pregabalin remains FDA-approved for FM across the Atlantic (guidelines; Carville 2021, PMID 33883123; Korwisi 2021, PMID 34712885). Whether Tonmya will be submitted to or accepted by EMA is unknown [unverified].

Open questions

  • Can responders be identified prospectively? Every review notes "a minority benefit substantially" (Welsch 2018, PMID 29489029; Derry 2016, PMID 27684492); no validated baseline predictor (phenotype, QST, comorbidity profile) exists — connects to biomarkers.
  • Does targeting sleep beat targeting pain? TNX-102 SL's approval rests on a sleep-centric mechanism (Lederman 2026, PMID 40627411); head-to-head against duloxetine or amitriptyline has never been run.
  • Is combination pharmacotherapy worth it at scale? One positive n=41 crossover (Gilron 2016, PMID 26982602) vs an empty Cochrane review (Thorpe 2018, PMID 29457627).
  • Why did LDN's effect shrink from d≈0.5–1 (pilot) to 0.23 (confirmatory)? Small-study bias, dose (4.5 vs 6 mg), or outcome choice (Bruun 2024, PMID 38258677; Hegde 2025, PMID 40540205)?
  • Would EMA approve any current FM drug under 2025 evidentiary standards, and should FDA's acceptance of ~0.5/10 deltas be recalibrated against the 18.6% placebo ≥50%-response rate (Häuser 2012, PMID 23137770)?
  • What are long-term (>1 year) benefits and harms of any FM drug? No reliable evidence exists for any agent (Birkinshaw 2023, PMID 37160297).

References

  1. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for fibromyalgia in adults. Cochrane Database Syst Rev. 2015 (record republished 2019);5(7):CD011824. PMID 35658166
  2. Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018;2:CD010292. PMID 29489029
  3. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;1:CD007115. PMID 24385423
  4. Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2015;10:CD008244. PMID 26482422
  5. Derry S, Cording M, Wiffen PJ, Law S, Phillips T, Moore RA. Pregabalin for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2016;9:CD011790. PMID 27684492
  6. Cooper TE, Derry S, Wiffen PJ, Moore RA. Gabapentin for fibromyalgia pain in adults. Cochrane Database Syst Rev. 2017;1:CD012188. PMID 28045473
  7. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. 2004;51:9-13. PMID 14872449
  8. Häuser W, Bernardy K, Üçeyler N, Sommer C. Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis. JAMA. 2009;301:198-209. PMID 19141768
  9. Birkinshaw H, Friedrich CM, Cole P, et al. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database Syst Rev. 2023;5:CD014682. PMID 37160297
  10. Nüesch E, Häuser W, Bernardy K, Barth J, Jüni P. Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis. Ann Rheum Dis. 2013;72:955-62. PMID 22739992
  11. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-73. PMID 15818684
  12. Crofford LJ, Mease PJ, Simpson SL, et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136:419-431. PMID 18400400
  13. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5-15. PMID 16298061
  14. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008;30:1988-2004. PMID 19108787
  15. Lederman S, Arnold LM, Vaughn B, Kelley M, Sullivan GM. Efficacy and safety of sublingual cyclobenzaprine for the treatment of fibromyalgia: results from a randomized, double-blind, placebo-controlled trial (RELIEF). Arthritis Care Res (Hoboken). 2023;75:2359-2368. PMID 37165930
  16. Lederman S, Arnold LM, Vaughn B, Engels JM, Kelley M, Sullivan GM. Pain relief by targeting nonrestorative sleep in fibromyalgia: a phase 3 randomized trial of bedtime sublingual cyclobenzaprine (RESILIENT). Pain Med. 2026;27:86-94. PMID 40627411
  17. Al-Qudah AA, Al-Hanaktah M. Short-term efficacy and safety of sublingual cyclobenzaprine for fibromyalgia: a systematic review and meta-analysis. Clin Rheumatol. 2026;45:1947-1957. PMID 41318845
  18. Maggi BG, Lima NL, de Lara LHC, et al. Efficacy and safety of TNX-102 SL in patients with fibromyalgia: a systematic review and meta-analysis. Pain Manag. 2025;15:1055-1063. PMID 41047726
  19. Sullivan GM, Meibohm B, Gould E, Daugherty BL, Lederman S. Steady-state pharmacokinetic properties of TNX-102 SL, a sublingual tablet formulation of cyclobenzaprine hydrochloride, with daily dosing in healthy volunteers. Clin Pharmacol Drug Dev. 2026;15:e70060. PMID 41948806
  20. Daugherty BL, Meibohm B, Sullivan GM, Gould EM, Lederman S. Single-dose pharmacokinetic assessment of TNX-102 SL (cyclobenzaprine HCl sublingual tablets). Clin Pharmacol Drug Dev. 2026;15:e70034. PMID 41749492
  21. Walitt B, Urrútia G, Nishishinya MB, Cantrell SE, Häuser W. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015;6:CD011735. PMID 26046493
  22. da Rocha AP, Mizzaci CC, Nunes Pinto ACP, et al. Tramadol for management of fibromyalgia pain and symptoms: systematic review. Int J Clin Pract. 2020;74:e13455. PMID 31799728
  23. Russell IJ, Perkins AT, Michalek JE. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2009;60:299-309. PMID 19116896
  24. Gaskell H, Moore RA, Derry S, Stannard C. Oxycodone for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2016;9:CD012329. PMID 27582266
  25. Goldenberg DL, Clauw DJ, Palmer RE, Clair AG. Opioid use in fibromyalgia: a cautionary tale. Mayo Clin Proc. 2016;91:640-8. PMID 26975749
  26. Derry S, Wiffen PJ, Häuser W, et al. Oral nonsteroidal anti-inflammatory drugs for fibromyalgia in adults. Cochrane Database Syst Rev. 2017;3:CD012332. PMID 28349517
  27. Clark S, Tindall E, Bennett RM. A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis. J Rheumatol. 1985;12:980-3. PMID 3910836
  28. Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W. Cannabinoids for fibromyalgia. Cochrane Database Syst Rev. 2016;7:CD011694. PMID 27428009
  29. Giossi R, Carrara F, Padroni M, et al. Systematic review and meta-analysis seem to indicate that cannabinoids for chronic primary pain treatment have limited benefit. Pain Ther. 2022;11:1341-1358. PMID 36129666
  30. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia. Arthritis Rheum. 2013;65:529-38. PMID 23359310
  31. Due Bruun K, Christensen R, Amris K, et al. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. 2024;6:e31-e39. PMID 38258677
  32. Hegde NC, Mishra A, V D, et al. Low dose naltrexone in the management of chronic pain syndrome: a meta-analysis of randomized controlled clinical trials. Curr Pain Headache Rep. 2025;29:96. PMID 40540205
  33. Gouda AHK, Aitcheson NEC, Steadman KJ. Low-dose naltrexone: what is the evidence? A narrative review. Adv Ther. 2026;43:2852-2870. PMID 42060160
  34. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. Pain. 2016;157:1532-40. PMID 26982602
  35. Thorpe J, Shum B, Moore RA, Wiffen PJ, Gilron I. Combination pharmacotherapy for the treatment of fibromyalgia in adults. Cochrane Database Syst Rev. 2018;2:CD010585. PMID 29457627
  36. Cui Z, Zhao Y, Novick D, Faries D. Predictors of duloxetine adherence and persistence in patients with fibromyalgia. J Pain Res. 2012;5:193-201. PMID 22792005
  37. Kleinman NL, Sanchez RJ, Lynch WD, et al. Health outcomes and costs among employees with fibromyalgia treated with pregabalin vs. standard of care. Pain Pract. 2011;11:540-51. PMID 21392253
  38. Häuser W, Sarzi-Puttini P, Tölle TR, Wolfe F. Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. Clin Exp Rheumatol. 2012;30(6 Suppl 74):78-87. PMID 23137770
  39. Briley M. Drugs to treat fibromyalgia - the transatlantic difference. Curr Opin Investig Drugs. 2010;11:16-8. PMID 20047155
  40. Calandre EP, Rico-Villademoros F, Slim M. An update on pharmacotherapy for the treatment of fibromyalgia. Expert Opin Pharmacother. 2015;16:1347-68. PMID 26001183
  41. Sommer C, Alten R, Bär KJ, et al. [Drug therapy of fibromyalgia syndrome: updated guidelines 2017]. Schmerz. 2017;31:274-284. PMID 28493231
  42. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord. 2007;8:27. PMID 17349056
  43. Carville S, Constanti M, Kosky N, Stannard C, Wilkinson C. Chronic pain (primary and secondary) in over 16s: summary of NICE guidance. BMJ. 2021;373:n895. PMID 33883123
  44. Korwisi B, Barke A, Kharko A, et al. Not really nice: a commentary on the recent version of NICE guidelines [NG193] by the Pain Net. Pain Rep. 2021;6:e961. PMID 34712885
  45. Abd-Elsayed A, Knezic A, Asfour J, Dewan P, Hasoon J, Reilly M. Sublingual cyclobenzaprine for fibromyalgia: pharmacokinetic rationale, clinical evidence, and place in therapy. Curr Pain Headache Rep. 2026;30(1). PMID 42479282
  46. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med. 2003;114:537-45. PMID 12753877
  47. Staud R. Sodium oxybate for the treatment of fibromyalgia. Expert Opin Pharmacother. 2011;12:1789-98. PMID 21679091
  48. [No authors listed]. Sodium oxybate: not authorised for fibromyalgia. Prescrire Int. 2012;21(133):290. PMID 23373093